This phase II trial studies how well tumor-infiltrating lymphocytes (TIL) after combination chemotherapy works in treating patients with melanoma that has spread to other places in the body. Biological therapies, such as TIL, may stimulate the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving TIL after combination chemotherapy may kill more tumor cells.

Patients receive cyclophosphamide IV on days -7 to -6 and fludarabine phosphate IV on days -5 to -1. Patients undergo TIL infusion over 30-60 minutes on day 0 and receive aldesleukin IV every 8 hours on days 1-5 for up to a maximum of 14 doses.

Drug: Cyclophosphamide

Given IV

Drug: Fludarabine Phosphate

Given IV

Other Names:

2-F-ara-AMP

Beneflur

SH T 586

Biological: Therapeutic Tumor Infiltrating Lymphocytes

Undergo TIL infusion

Other Name: Tumor Infiltrating Lymphocytes

Biological: Aldesleukin

Given IV

Other Name: Ro-236019

Other: Laboratory Biomarker Analysis

Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Examine the anti-tumor efficacy of cellular adoptive immunotherapy in metastatic melanoma patients using autologous tumor-infiltrating lymphocytes with a lymphodepleting conditioning regimen of cyclophosphamide and fludarabine (fludarabine phosphate), and followed by adjuvant high-dose interleukin (IL)-2 (aldesleukin).

SECONDARY OBJECTIVES:

I. Determine the in vivo persistence of transferred tumor-infiltrating lymphocytes.

II. Examine the safety of cellular adoptive immunotherapy in melanoma patients using autologous tumor-infiltrating lymphocytes, preceded by a lymphodepleting conditioning regimen of cyclophosphamide and fludarabine, and followed by adjuvant high-dose IL-2.

III. Evaluate for molecular tumor markers and immunohistochemical features that correlate with in vivo persistence and anti-tumor efficacy.

OUTLINE:

Patients receive cyclophosphamide intravenously (IV) on days -7 to -6 and fludarabine phosphate IV on days -5 to -1. Patients undergo TIL infusion over 30-60 minutes on day 0 and receive aldesleukin IV every 8 hours on days 1-5 for up to a maximum of 14 doses.

After completion of study treatment, patients are followed up at 6, 12, and 24 weeks.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Step I Inclusion Criteria:

Stage IV melanoma or stage III melanoma that is unlikely to be cured by surgery

Able to tolerate high-dose cyclophosphamide, fludarabine and high-dose IL-2

Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

Patients must have an magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET) of the brain within 2 months before consenting if known history of brain metastasis or if clinically indicated; if new lesions are present, principal investigator (PI) or designee should make final determination regarding enrollment

Patients must have a site of metastatic disease that can be safely resected or biopsied for tissue sufficient for TIL harvest

A stress cardiac test (e.g., stress treadmill, stress thallium, stress multi gated acquisition scan [MUGA], dobutamine echocardiogram) to rule out cardiac ischemia within 4 months before Step I is required for patients with a history of cardiac disease

Step II Inclusion Criteria:

Patients must have measurable metastatic melanoma

Able to tolerate high-dose cyclophosphamide, fludarabine, and high-dose IL-2

ECOG performance status of 0-1 at time of lymphodepletion

Patients must have brain imaging by MRI, CT or PET within 30 days prior to lymphodepletion; patients may have asymptomatic brain lesions that are < 1 cm each, if there is no mass effect and no edema; 1-3 lesions that are > 1 cm that have been irradiated and in the opinion of the investigator no longer represents active disease will also be allowed

Ejection fraction < 45% (echocardiogram or MUGA), although any patient with an ejection fraction between 45-49% must receive clearance by a cardiologist to be eligible for this trial

Clinically significant autoimmune disorders or conditions of immunosuppression; patients with acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV)-1 associated complex or known to be HIV antibody seropositive or known to be recently polymerase chain reaction (PCR)+ for hepatitis B or C are not eligible for this study; the severely depressed or altered immune system found in these patients and the possibility of premature death would compromise study objectives

Clinically significant psychiatric disease which, in the opinion of the PI or sub-investigator (I), would render immunotherapy and its potential sequelae unsafe or compliance with procedural requirements unlikely

Step II Exclusion Criteria:

Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative pregnancy test within 7 days prior to entry; patients of both genders must practice birth control during treatment and for four months after treatment

Calculated creatinine clearance (eGFR) < 60 ml/min

AST/ALT > 3 x upper limit of normal

Total bilirubin > 2.0 mg/dl, except in patients with Gilbert's syndrome whose total bilirubin must not exceed 3.0 mg/dl)

Significant cardiovascular abnormalities as defined by any one of the following:

Congestive heart failure

Clinically significant hypotension

Cardiac ischemia, or symptoms of coronary artery disease

Presence of cardiac arrhythmias on EKG requiring drug therapy

Ejection fraction < 45% (echocardiogram or MUGA), although any patient with an ejection fraction between 45-49% must receive clearance by a cardiologist to be eligible for this trial

Absolute neutrophil count less than 1000/mm^3

Platelet count less than 100,000/mm^3

Hemoglobin less than 10.0 g/dl

Untreated central nervous system metastases that are either symptomatic or greater than 1 cm at time of therapy; 1-3 lesions that are > 1cm that have been treated with stereotactic radiosurgery (SRS) and in the opinion of the PI or sub-I no longer represent active disease may be allowed

Systemic cancer therapy (standard or experimental), including cytotoxic chemotherapy or IL-2, received less than 4 weeks or checkpoint blocking agents (e.g., cytotoxic T-lymphocyte protein [CTLA]-4 or programmed cell death protein [PD]1/PD-ligand [L]1 inhibitors) received less than 6 weeks prior to lymphodepletion, with the exception of targeted therapies

Clinically significant autoimmune disorders or conditions of immunosuppression; patients with AIDS or HIV-1 associated complex or known to HIV antibody seropositive or known to be recently PCR+ for hepatitis B or C virus are not eligible for this study; virology testing will be done within 6 months of T cell infusion; the severely depressed or altered immune system found in these patients and the possibility of premature death would compromise study objectives

Any other significant medical or psychological conditions that would make the patient unsuitable candidate for cell therapy at the discretion of the PI

Contacts and Locations

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01807182